tbuckley/cabot-search huggingface dataset:
Abstract 2185: Septin isoform expression as a potential biomarker for differential response to microtubule targeted chemotherapy in breast cancer
Authors: Jacob N. Essif, Samantha S. Yee, April Risinger
Journal: Cancer Research (2023)

Abstract The primary cause of cancer-associated death is due to the development of metastatic disease. Metastasis is a multistage process requiring displacement of cells from the primary tumor, survival in circulation, and adhesion and growth in a secondary location. Reorganization of both the actin and microtubule cytoskeleton is critical for metastasis of solid tumors. Drugs that inhibit microtubule dynamics, including microtubule stabilizers and destabilizers, are used to treat metastatic breast cancer, however there is no rationale to guide the choice among these drugs. Septins, a class of small GTPases, interact with both microtubules and actin to functionally link these cytoskeletal components. Expression of a specific isoform, septin9_i1, is associated with breast cancer development, migration, and drug resistance. This isoform is unique among septins in that it contains a specific microtubule binding domain required for association of septins with microtubules. We found that microtubule stabilizing or destabilizing chemotherapeutics currently used to treat metastatic breast cancer promoted respective microtubule or actin localization of oncogenic septins, particularly when septin9_i1 was expressed. This differential cellular distribution correlated with our finding that microtubule destabilizers were more effective than stabilizers at inhibiting the migration of septin9_i1 expressing breast cancer cells in vitro whereas the drugs were equally effective in isogenic cells depleted of septin9_i1. We are currently testing the hypothesis that septin9_i1 promotes in vivo metastasis of breast tumors and that microtubule destabilizers will be more effective than stabilizers at inhibiting this metastasis. This supports our ongoing clinical investigations to determine whether septin9_i1 expression could be used as a predictive biomarker to guide the selection among microtubule-targeted chemotherapeutics, which is significant as there is currently no molecular guidance to inform on this choice. Our findings will promote the more targeted and rational use of this highly used but mechanistically underappreciated class of chemotherapy. Citation Format: Jacob N. Essif, Samantha S. Yee, April Risinger. Septin isoform expression as a potential biomarker for differential response to microtubule targeted chemotherapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2185.
Abstract 4945: Inhibition of wild-type PI3Kα signaling is required for durable efficacy in PI3Kα mutant cancer cells due to robust re-activation of wild-type PI3Kα signaling
Authors: John R. MacDougall, Mengqi Zhong, Hanne Merritt, Joselyn S. Del Cid, John Bradley, Raymond Mak, Neil Dhawan, Wei Chen
Journal: Cancer Research (2023)

Abstract PI3Kα is the most mutated oncogene with a high mutation rate in breast, lung, colorectal, gastric, bladder, and other tumor types. However, current inhibitors have had little efficacy in the clinic due to their inability to achieve maximal PI3Kα target engagement in a highly specific and durable manner. Contributing to this is that most PI3Kα mutant cancer cells are prone to robust pathway feedback and re-activation of remaining wild type PI3Kα signaling upon initial inhibition. We have analyzed pathway feedback in a variety of PI3Kα mutant cancer cell lines across multiple diverse indications and found this to be a common trait among PI3Kα mutant cancer cells. Additionally, when the mutant PI3Kα protein alone is targeted in these cells using mutant-specific inhibitors, we observed robust pathway re-activation and tumor cell proliferation. In contrast, TOS-358, a highly selective first-in-class covalent PI3Kα inhibitor, achieved complete inhibition of both PI3Kα mutant and wild type signaling and this correlated with the induction of cell cycle arrest and cell death across a wide variety of PI3Kα mutant tumor types. Furthermore, stimulation of PI3Kα signaling with serum rapidly re-activated the PI3K-AKT pathway in the presence of reversible and mutant specific inhibitors. Covalent molecules (namely TOS-358) achieved complete inhibition of pathway signaling in this format. Overall, this reveals the need to achieve sustained inhibition of both PI3Kα mutant and wild type signaling to achieve durable efficacy in PI3Kα mutant tumors. Citation Format: John R. MacDougall, Mengqi Zhong, Hanne Merritt, Joselyn S. Del Cid, John Bradley, Raymond Mak, Neil Dhawan, Wei Chen. Inhibition of wild-type PI3Kα signaling is required for durable efficacy in PI3Kα mutant cancer cells due to robust re-activation of wild-type PI3Kα signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4945.
Abstract 1218: Mercury(II)-induced abnormalities in processing of topoisomerase I-mediated DNA damage
Authors: Giorgiana Madalina Ursu, Anna M. Cyran, Anatoly Zhitkovich
Journal: Cancer Research (2023)

Abstract Mercury (Hg) is a persistent environmental pollutant that has long been associated with neurotoxic and other noncancer health effects in exposed populations. Recent large epidemiological studies using different internal indices of Hg exposure have found significantly elevated risks for skin cancers in both men and women. To understand potential carcinogenic mechanisms for Hg(II), we examined its mutagenicity and impact on processing of different types of DNA damage. In agreement with its lack of DNA reactivity, we found that Hg(II) was not mutagenic at the mammalian Hprt locus and did not change DNA incorporation of rNMPs which are the most abundant endogenous nucleotide abnormalities in the genome. We next tested the impact of Hg(II) at nontoxic or only mildly toxic concentrations on sensitivity of cells to several genotoxicants producing specific classes of DNA damage. We found that even nontoxic concentrations of Hg(II) impaired cellular resistance to topoisomerase I-mediated DNA damage in human epidermal keratinocytes. Hg(II) had no significant effect on cytotoxicity of topoisomerase II-mediated DNA lesions and examination of numerous components of DNA damage response activated by topoisomerase II-targeting drugs showed no major differences between control and Hg(II)-exposed cells. In contrast, Hg(II)-treated keratinocytes displayed a distorted DNA damage response to topoisomerase I-produced DNA damage, manifested in a misbalanced activation of ATM and ATR targets. Consistent with their lower survival, Hg(II)-treated cells accumulated higher levels of toxic DNA double-strand breaks (DSBs). Further analyses indicated that Hg(II) caused impartment of DNA repair of replication-associated DSBs. Thus, although Hg(II) is not directly genotoxic, it can increase genomic instability by interfering with accurate processing of endogenous DNA damage produced by topoisomerase I. Citation Format: Giorgiana Madalina Ursu, Anna M. Cyran, Anatoly Zhitkovich. Mercury(II)-induced abnormalities in processing of topoisomerase I-mediated DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1218.
Abstract 2429: AGPAT4 as a novel metabolic driver of oncogenic stemness and dedifferentiation in hepatocellular carcinoma
Authors: Kai Yu Ng, Tsz-Lok Fong, Ya Gao, Tin-Lok Wong, Yuan Gao, Jing-Ping Yun, Xin-Yuan Guan, Ming Liu, Clive YS Chung, Stephanie Ma
Journal: Cancer Research (2023)

Abstract The liver is an unique organ in that it is responsible for many metabolic functions. During HCC development, these metabolic machineries are extensively reprogrammed to support the insatiable nutrient requirement of HCC. Cancer stem cells (CSCs) are a small and elusive subpopulation of self-renewing cancer cells with remarkable ability to initiate, propagate, and spread the malignant disease. Liver CSCs reprogram their metabolic pathways to match with the increased metabolic needs for cancer cell survival under adverse conditions. Identifying novel metabolic targets that are related to stemness can offer promising strategies for targeting CSCs and hence to kill and to control their growth. In this study, pathway enrichment analysis of genes that linked metabolism and stemness identified aberrant glycerophospholipid metabolism of which AGPAT4 ranked a top-hit. AGPAT4 upregulation in HCC is tightly correlated with aggressive clinical features, including survival, metastasis, and stemness signatures. Expression of AGPAT4 peaked during early liver progenitor development, decreased during hepatocyte maturation and increased progressively from well-differentiated to poorly differentiated HCCs. Enrichment of AGPAT4 in HCC was mediated by promoter binding of SOX9 to drive AGPAT4 transcriptional activity. AGPAT4 inhibition could mitigate tumor initiation, self-renewal, metastasis and sorafenib resistance. Mechanistic studies revealed an AGPAT4-mediated phosphatidic acid production axis to promote HCC through regulating mTOR signaling. Inhibition of Agpat4 by AAV8 shRNA reduced tumorigenicity and stemness, and sensitized HCC tumors to sorafenib. AGPAT4 overexpression was able to predict sorafenib response in the clinic. Through high-throughput screening coupled with activity-based protein profiling, a cysteine-reacting compound with high binding affinity and selectivity towards AGPAT4 was identified and found to work synergistically with sorafenib to supress HCC. To conclude, AGPAT4 is a novel metabolic driver of oncogenic stemness, dedifferentiation and metastasis in HCC. AGPAT4-induced tumor lineage plasticity may represent an Achilles heel for HCC. Inhibition of AGPAT4 may widen the therapeutic window for sorafenib treatment in the clinic. Citation Format: Kai Yu Ng, Tsz-Lok Fong, Ya Gao, Tin-Lok Wong, Yuan Gao, Jing-Ping Yun, Xin-Yuan Guan, Ming Liu, Clive YS Chung, Stephanie Ma. AGPAT4 as a novel metabolic driver of oncogenic stemness and dedifferentiation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2429.
Abstract 4127: ANV600 is a potent, C<i>is</i>-signaling, non-alpha IL-2 agonist which efficiently expands intratumoral stem-like CD8 T cells
Authors: Patrizia Murer, Ulisse Salazar, Nicole Egli, Laetitia Petersen, Pia Neubert, Kirsten Richter, Christian Stocker, Alexander Rau, Andreas Katopodis, Christoph Huber
Journal: Cancer Research (2023)

Abstract Non-alpha IL-2-based therapeutic modalities with preferential signaling through the IL-2 beta(CD122)/gamma(CD132) receptor are in clinical development and have the potential to substantially increase the therapeutic index of recombinant IL-2 (aldesleukin) for cancer therapy. ANV600 is a novel bispecific compound, which features an anti-IL-2 antibody/IL-2 fusion protein and a proprietary hPD-1 binding moiety for specific delivery of the non-alpha IL-2 to tumor antigen experienced PD-1+ T cells. Compared to the untargeted control, ANV600 has increased potency to induce STAT5 phosphorylation in human PD-1+CD8 T cells in vitro. At the same time, stimulation with ANV600 results in markedly reduced STAT5 phosphorylation on Treg cells compared to aldesleukin. In activated human PBMCs, ANV600 induces PD-1 co-internalization with the CD122-CD132 complex, reducing detectable PD-1 on CD8 and CD4 T-cells. Surface PD-1 levels decrease is not observed on cells incubated with untargeted bispecific compound. In transgenic human PD-1 mice ANV600 treatment leads to marked tumor growth retardation in the B16F10 and MC38 subcutaneous tumor models compared to untargeted compound and vehicle. Immunophenotyping of the tumor infiltrating lymphocytes revealed a dose-dependent increase of intratumoral stem-like PD-1+T cells and cytotoxic GrzB+PD-1+T cells in mice treated with ANV600. ANV600 has potent and selective effects on antigen-experienced CD8 T cells both in human PBMCs and mouse syngeneic tumor models. This agent may be a promising anti-tumor therapeutic against poorly immunogenic tumors and warrants further pharmaceutical development. Citation Format: Patrizia Murer, Ulisse Salazar, Nicole Egli, Laetitia Petersen, Pia Neubert, Kirsten Richter, Christian Stocker, Alexander Rau, Andreas Katopodis, Christoph Huber. ANV600 is a potent, Cis-signaling, non-alpha IL-2 agonist which efficiently expands intratumoral stem-like CD8 T cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4127.
Abstract 4820: The disassembly of amyloid-bodies
Authors: Chloe Kirk, Michael Bokros, Alex Grunfeld, Stephen Lee
Journal: Cancer Research (2023)

Abstract The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various physiological and pathological settings, including development, cancer and neurological disorders. We recently reported the discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as “junk” DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts the nucleolus into Amyloid-bodies: a molecular prison of immobilized proteins in an amyloid-like state. This conserved post-translational regulatory pathway enables cells to rapidly and reversibly store an array of endogenous proteins in Amyloid-bodies and enter a dormant-like phenotype in response to severe environmental insults. While many membrane-less compartments have been described as liquid-like (e.g., stress granules, P-bodies, germ cell granules), our discovery of Amyloid-bodies provided evidence of an amyloidogenic process that can physiologically transition biological matter to a solid-like state. The ability of mammalian cells to efficiently dissemble Amyloid-bodies raises a fundamental question: Are mammalian cell disaggregases involved in Amyloid-body disassembly? Here, we show that Amyloid-bodies undergo a solid-to-liquid-phase transition to release sequestered proteins and restore nucleolar functions. An RNAi screened identified key Heat Shock Proteins (Hsps) that remodel Amyloid-bodies back to the liquid nucleoli on stress termination. The composition of mammalian disaggregases differs considerably from non-metazoans and those involved in disassembly of pathological amyloids in vitro. Activation of mammalian disaggregases and Amyloid-body disassembly is dependent on ATP concentration. Conceptually, this work identifies metazoan disaggregases challenging the widely accepted paradigm that the amyloid state is irreversible in mammalian cells. The data also provides alternative insights into pathogenic amyloids by examining their disassembly in cellular systems. Citation Format: Chloe Kirk, Michael Bokros, Alex Grunfeld, Stephen Lee. The disassembly of amyloid-bodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4820.
Abstract 1752: Darolutamide reverses osimertinib resistance in non-small cell lung cancer
Authors: John C. Schmitz, Guojing Zhang, Zhentao Liu, Yufei Huang, Gabriel Sica, Shi-Yong Sun, Taofeek K. Owonikoko
Journal: Cancer Research (2023)

Abstract Targeted therapies, such as EGFR inhibitors, have improved survival for patients with non-small cell lung cancer (NSCLC). Overall cure rates remain low due to eventual development of resistance. Osimertinib is a third-generation EGFR inhibitor that overcomes T790M-mediated resistance to earlier generation EGFRi. However, resistance to osimertinib has also emerged through mechanisms that are EGFR-dependent and EGFR-independent. To uncover novel strategies to overcome osimertinib resistance, we explored androgen receptor (AR) antagonists in combination with osimertinib as recent studies have demonstrated AR inhibition enhanced TKI-targeted therapy. For these experiments, we utilized lab-derived osimertinib-resistant PC9-AR and HCC827-AR NSCLC cell lines and matching parental lines in both in vitro and in vivo model systems. Clonogenic assays revealed that darolutamide in combination with osimertinib synergistically suppressed clonal growth in resistant cell lines. Similar results were observed with the combination of enzalutamide and osimertinib. Given this result, we next wanted to establish whether the promising in vitro activity of this combination translates into antitumor efficacy in vivo. Mice bearing either HCC827AR or PC9AR xenografts were treated orally daily with both drugs. At the doses administered, neither drug alone had antitumor activity. However, the combination significantly delayed tumor growth by more than 60%. We confirmed this ability to reverse resistance as a class effect using a different AR antagonist, enzalutamide in PC9AR-bearing mice. Significant tumor growth inhibition was observed with the combination of enzalutamide and osimertinib. To investigate the mechanism by which this combination may reverse osimertinib-resistance, RNA-seq studies were performed following drug exposure in vitro using parental and resistant cell lines under various experimental conditions. Comparison of gene expression profiles between parental and resistant cell lines under different therapeutic pressure and pathway enrichment analysis revealed important differentially expressed genes pointing plausible activated pathways that underline osimertinib resistance. AR antagonists have the potential to reverse EGFR inhibitor resistance in treatment of EGFR-mutant NSCLC. Citation Format: John C. Schmitz, Guojing Zhang, Zhentao Liu, Yufei Huang, Gabriel Sica, Shi-Yong Sun, Taofeek K. Owonikoko. Darolutamide reverses osimertinib resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1752.
Abstract 5376: Protein structure-based modeling to improve MHC class I epitope predictions
Authors: Eric A. Wilson, John Kevin Cava, Diego Chowell, Abhishek Singharoy, Karen S. Anderson
Journal: Cancer Research (2023)

Abstract The ability to accurately identify peptide ligands for a given major histocompatibility complex class I (MHC-I) molecule has immense value for targeted anticancer therapeutics. However, the highly polymorphic nature of the MHC-I protein makes universal prediction of peptide ligands challenging due to lack of experimental data describing most MHC-I variants. To address this challenge, we have developed a deep convolutional neural network, HLA-Inception, capable of predicting MHC-I peptide binding motifs using electrostatic properties of the MHC-I binding pocket. By approaching this immunological issue using molecular biophysics, we measure the impact of sidechain arrangement and topology on peptide binding, feature not captured by sequence-based MHC-I prediction methods. Through a combination of molecular modeling and simulation, 5821 MHC-I alleles were modeled, providing extensive coverage across human populations. Predicted peptide binding motifs fell into distinct clusters, each defined with different degrees of submotif heterogeneity. Peptide binding scores generated by HLA-Inception are strongly correlated with quantitative MHC-I binding data, indicating predicted peptides can be ranked, both within and between alleles. HLA-inception also showed high precision when predicting naturally presented peptides and can be used for rapid proteome-scale MHC-I peptide binding predictions. Finally, we show that the binding pocket diversity measured by HLA inception predicts response to checkpoint blockade. Citation Format: Eric A. Wilson, John Kevin Cava, Diego Chowell, Abhishek Singharoy, Karen S. Anderson. Protein structure-based modeling to improve MHC class I epitope predictions. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5376.
Abstract 5860: ZEB1-driven reconstruction of the hyaluronan network establishes a pro-metastatic microenvironment in lung adenocarcinoma
Authors: Sieun Lee, Jihye Park, Eun Ju Kim, Sungsoo Park, Jonathan M. Kurie, Young-Ho Ahn
Journal: Cancer Research (2023)

Abstract Hyaluronan, one of the major components of the extracellular matrix (ECM), surrounds and protects neighboring cells from diverse stresses. Hyaluronan promotes epithelial-to-mesenchymal transition (EMT) and metastasis in various epithelial cancers. However, the mechanism by which the hyaluronan network built up by cancer cells regulates cancer progression and metastasis in the tumor microenvironment has not been elucidated in detail. In this study, ITIH2, a hyaluronan-binding protein that participates in building a hyaluronan network, was confirmed to be secreted from mesenchymal-like lung cancer cells when co-cultured with cancer-associated fibroblasts. ITIH2 was transcriptionally upregulated by ZEB1, an EMT-inducing transcription factor. Hyaluronic acid synthase-2 (HAS2) was also up-regulated by ZEB1, and the expression of HAS2 and ZEB1 showed a positive correlation in the TCGA database. In addition, ZEB1 controlled alternative splicing and isoform expression of CD44, a hyaluronan receptor. Interestingly, ITIH2 knockdown and 4-methylumbelliferone (4-MU), a HAS inhibitor, reduced the formation of hyaluronan cables and inhibited the migration and invasion of lung cancer cells. Likewise, when lung cancer cells were treated with “Compound S,” an ITIH2 inhibitor predicted by a deep learning-based drug-target interaction algorithm, the formation of hyaluronan cables and cell migration were suppressed. In addition, the ITIH2 inhibitor prevented the growth of metastatic tumors in an orthotopic lung cancer mouse model. Collectively, the EMT signal controlled by ZEB1 establishes the pro-metastatic hyaluronan network in the tumor microenvironment, suggesting a novel strategy for targeting the hyaluronan network to suppress lung cancer progression and metastasis. Citation Format: Sieun Lee, Jihye Park, Eun Ju Kim, Sungsoo Park, Jonathan M. Kurie, Young-Ho Ahn. ZEB1-driven reconstruction of the hyaluronan network establishes a pro-metastatic microenvironment in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5860.